The current preferred treatment for Type II, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently no approved medications that adequately treat either Type II diabetes or obesity. The invention described herein is directed toward an effective and timely treatment for these serious diseases.
One therapeutic opportunity that has recently been recognized involves the relationship between adrenergic receptor stimulation and anti-hyperglycemic effects. Compounds that act as .beta..sub.3 receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis and serum glucose levels in animal models of Type II (non-insulin dependent) diabetes.
The .beta..sub.3 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the .beta..sub.1 and .beta..sub.2 receptor subtypes yet is considerably less abundant. The importance of the .beta..sub.3 receptor is a relatively recent discovery since the amino-acid sequence of the human receptor was only elucidated in the late 1980's. A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the .beta..sub.3 receptor. Despite these recent developments, there remains a need to develop a selective .beta..sub.3 receptor agonist which has minimal agonist activity against the .beta..sub.1 and .beta..sub.2 receptors. In addition, indolylpropanolamines have been disclosed by Beedle et. al. U.S. Pat. No. 5,013,761.
The present invention provides compounds which are selective .beta..sub.3 receptor agonists. As such, the compounds effectively lead to an increase in insulin sensitivity and are useful in treating Type II diabetes and other ailments implicated by the .beta..sub.3 receptor, without cardiac or tremor-related side effects.